RAG1 is the catalytic component of the RAG recombinase complex essential for V(D)J recombination in developing B and T lymphocytes 1. RAG1 mediates DNA binding to conserved recombination signal sequences (RSS) and catalyzes double-strand DNA breaks between RSS and coding segments through a two-step nicking and hairpinning mechanism, generating the structural diversity of immunoglobulin and T-cell receptor genes 2. Beyond endonuclease activity, RAG1 functions as an E3 ubiquitin-protein ligase that monoubiquitinates histone H3, a modification required for the joining phase of V(D)J recombination. RAG1 also enforces allelic exclusion by inducing ATM-dependent repositioning of unrearranged immunoglobulin alleles to heterochromatin, ensuring single B-cell receptor expression 2. Pathogenic RAG1 mutations cause a spectrum of primary immunodeficiencies ranging from severe combined immunodeficiency (SCID) to delayed-onset disease with autoimmunity and granulomas 2. Notably, residual recombination activity of mutant RAG1 proteins correlates with disease severity, enabling phenotype prediction 2. Currently, hematopoietic stem cell transplantation remains the only cure for severe RAG1 deficiency, though emerging gene therapy approaches using viral vectors or CRISPR/Cas9-mediated correction show clinical promise 3. CRISPR/Cas9 gene editing strategies targeting in-frame exon 2 integration achieve physiologic RAG1 expression and functional rescue in patient-derived cells 4.